Statins, inhibitors of HMG CoA reductase, a key enzyme in the cholesterol synthetic pathway, effectively prevent both primary and secondary coronary vascular disease. The beneficial effect of the statins is not all due to their cholesterol lowering function. Recently multiple immunosuppressive effects of statins have been demonstrated both in models of inflammation and of vascular injury. Most of these effects are due to decreased synthesis of mevalonate-derived intermediates that are required for full activation of small GTP binding proteins such as Rho and Ras. Thus there has been increasing interest in possible clinical utility of statins for autoimmune diseases. Our laboratory is interested in developing therapeutic combination regimens of drugs that act on different pathways of immune activation and target organ damage. We have previously focused on the mechanism of action of biologic agents that inhibit costimulatory pathways of B and T cell activation. In this proposal we will ask whether treatment with statins will synergize with costimulatory blockade for the treatment of two different manifestations of SLE; inflammatory renal disease and non-inflammatory vasculopathy. The initiation of both these SLE manifestations is immune mediated but the tissue response to autoantibody-mediated damage is different in each case. Both however may be susceptible to the beneficial effects of statins. In aim 1 we will determine the effect of statins in SLE nephritis. We will ask whether statins will synergize with CTLA4Ig in prevention of SLE nephritis and whether they will help maintain remission of nephritis after treatment with a short course of CTLA4Ig and cyclophosphamide. Effects of therapy on immunologic parameters and effector responses in the kidney will be evaluated by a series of assays that are well established in the laboratory. In aim 2 we will utilize a murine model of vasculopathy induced by anti-phospholipid antibodies and ask whether statins, with or without CTLA4Ig, will prevent disease intitiation or progression. In aim 3 we will determine whether monocytes and dendritic cells from patients with inactive SLE are susceptible to the known immunoregulatory effects of statins and determine which statin is most potent. These studies will gather information that may support a clinical trial of statins in SLE patients.